Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:20][CH2:19][O:18][C:17]([NH:21]C(=O)C4C=CC=CC=4)=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12](I)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.[CH3:31][O:32][C:33]1[N:34]=[CH:35][C:36]([C:39]([NH2:41])=[O:40])=[N:37][CH:38]=1.N>C1COCC1.CO>[NH2:21][C:17]1[O:18][CH2:19][CH2:20][C@:15]2([C:4]3[C:5](=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[O:8][C:9]3[C:14]2=[CH:13][C:12]([NH:41][C:39]([C:36]2[CH:35]=[N:34][C:33]([O:32][CH3:31])=[CH:38][N:37]=2)=[O:40])=[CH:11][CH:10]=3)[N:16]=1
Reactant: O=C(NC1=N[C@@]2(CCO1)c1cc(I)ccc1Oc1ncc(Br)cc12)c1ccccc1
Reactant: COc1cnc(C(N)=O)cn1
Agent: N
Solvent: C1CCOC1
Solvent: CO
Product: COc1cnc(C(=O)Nc2ccc3c(c2)[C@@]2(CCOC(N)=N2)c2cc(Br)cnc2O3)cn1
Reaction time: 5 h

Procedure:
The title compound was synthesized analogous to step 1 (Method D) described in example 34, but using (S)—N-(3-bromo-7-iodo-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazin]-2′-yl)benzamide (88 mg, 0.153 mmol, Intermediate 24B) and 5-methoxypyrazine-2-carboxamide (28.1 mg, 0.183 mmol). The residue from step 1 was dissolved in THF (1 mL) and treated with ammonia (2.0 M solution in methanol; 1.145 mL, 2.291 mmol) at 50° C. After 12 hours another portion of ammonia, (2.0 M solution in methanol; 1.145 mL, 2.291 mmol) was added and the reaction mixture was allowed to stir for additional 5 hours The solvent was removed under reduced pressure and the residue was purified by preparative reversed-phase HPLC using a Phenomenex Gemini column, 10 micron, C18, 110 Å, 100×50 mm, 0.1% TFA in CH3CNH2O, gradient 10% to 100% over 20 min. The combined fractions were concentrated. The residue was dissolved in MeOH and loaded onto a Varian Bond Elut SCX column. The product was eluted with a 2M solution of NH3 in MeOH. 10 mg of (S)—N-(2′-amino-3-bromo-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazin]-7-yl)-5-methoxypyrazine-2-10 carboxamide were obtained as an off-white solid. MS m/z=497.1 [M]+. Calculated for C21H17BrN6O4: 497.30. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.82-1.92 (m, 1H) 1.94-2.04 (m, 1H) 4.08 (s, 3H) 4.11-4.18 (m, 1H) 4.20-4.30 (m, 1H) 7.31 (d, J=9.21 Hz, 1H) 7.69-7.77 (m, 2H) 7.94 (d, J=2.34 Hz, 1H) 8.18 (d, J=1.32 Hz, 1H) 8.32 (d, J=2.48 Hz, 1H) 9.04 (d, J=1.32 Hz, 1H) 9.55 (s, 1H).
Reaction SMILES: C(N(CC)CC)C.[C:8]([N:11]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:14]([CH2:23][C:24]([NH:26][C@@H:27]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:28][OH:29])=[O:25])[C:13](=[O:37])[CH:12]1[CH:38]([CH3:40])[CH3:39])(=[O:10])[CH3:9].O>CS(C)=O>[C:8]([N:11]1[CH:16]=[C:15]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:14]([CH2:23][C:24]([NH:26][C@@H:27]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:28]=[O:29])=[O:25])[C:13](=[O:37])[CH:12]1[CH:38]([CH3:40])[CH3:39])(=[O:10])[CH3:9]
Reactant: CC(=O)N1C=C(c2ccccc2)N(CC(=O)N[C@H](CO)Cc2ccccc2)C(=O)C1C(C)C
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)N1C=C(c2ccccc2)N(CC(=O)N[C@H](C=O)Cc2ccccc2)C(=O)C1C(C)C
Reaction time: 8 h
Yield: 46.3 %

Procedure:
Triethylamine (2.60 ml) is added to a solution of (2S)-2-{(3RS)-4-acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-3-phenyl-1-propanol (1.37 g, Compound No. 6-1) in dimethyl sulfoxide (16 ml). A sulfur trioxide-pyridine complex (1.7 g) is added to the mixture, and the whole is stirred overnight. Water is added to the reaction mixture, and the whole is stirred for one hour and extracted with ethyl acetate. The extract is washed with a saturated aqueous ammonium chloride solution, water and saturated brine successively and dried over anhydrous magnesium sulfate. The extract is concentrated under reduced pressure, and the resulting residue is purified by silica gel column chromatography to give the titled compound (631 mg).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[N-:9]=[N+:10]=[N-:11].[Na+]>CN(C=O)C>[N:9]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8])=[N+:10]=[N-:11]
Reactant: [N-]=[N+]=[N-]
Reactant: OCCCCCCBr
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCCCCCO
Temperature: 50 °C
Reaction time: 72 h
Yield: 99 %

Procedure:
6-Bromo-1-hexanol (5.00 g, 27.6 mmol) was dissolved in 12 mL of DMF. To this solution, sodium azide (4.00 g, 61.5 mmol) was added and the mixture was stirred at 50° C. for 3 days. The mixture was concentrated by evaporation, and distilled water (10 mL) was added thereto. This aqueous solution was extracted six times with diethyl ether, and the combined organic extracts were dried over magnesium sulfate, followed by evaporation to give a product (6-azido-1-hexanol). The yield was 99% or more.
Reaction SMILES: Br.Br[CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:18](=[O:28])[C:19]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:20][NH:21][CH:22]=2)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C=O)C>[F:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[C:18](=[O:28])[C:19]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:20][N:21]([CH2:3][C:4]3[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=3)[CH:22]=2)=[CH:15][CH:16]=1
Reactant: CCOC(=O)c1c[nH]cc(-c2ccc(F)cc2)c1=O
Reactant: BrCc1ccncc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(Cc2ccncc2)cc(-c2ccc(F)cc2)c1=O
Temperature: 100 °C
Reaction time: 8 h
Yield: 46.7 %

Procedure:
4-(Bromomethyl)pyridine hydrobromide (290 mg) was added to a suspension of ethyl 5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxylate (200 mg) and cesium carbonate (998 mg) in DMF (5 ml) at room temperature. The reaction mixture was stirred at 100° C. overnight. The reaction mixture was returned to room temperature and diluted by adding ethyl acetate. The organic layer was washed with water and brine and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography [chloroform:methanol=10:0->19:1->9:1 (v/v)], and the eluate was concentrated under reduced pressure. The residue was purified by PLC [dichloromethane:methanol=10:1 (v/v)] to give 126 mg of the title compound as an oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:27])[C:5]([NH:17][C@H:18]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH3:19])=[N:6][C:7]=1[NH:8][C:9]1[CH:13]=[C:12]([CH:14]2[CH2:16][CH2:15]2)[NH:11][N:10]=1.[C:28](O)(=O)C.C(N)=N.C([O-])(O)=O.[Na+].CCOC(C)=O>CCO>[Cl:1][C:2]1[CH:3]=[C:4]2[N:27]=[CH:28][N:17]([C@H:18]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[CH3:19])[C:5]2=[N:6][C:7]=1[NH:8][C:9]1[CH:13]=[C:12]([CH:14]2[CH2:16][CH2:15]2)[NH:11][N:10]=1
Reactant: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(Cl)cc1N)c1ccc(F)cc1
Reactant: CC(=O)O
Agent: N=CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: C[C@@H](c1ccc(F)cc1)n1cnc2cc(Cl)c(Nc3cc(C4CC4)[nH]n3)nc21
Temperature: 25 °C
Yield: 47.5 %

Procedure:
A mixture of (S)-5-chloro-N6-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-(1-(4-fluorophenyl)ethyl)pyridine-2,3,6-triamine (Method 27; 0.300 g, 0.77 mmol) and formamidine acetate (0.129 g, 1.24 mmol) in EtOH (5 ml) was heated at reflux overnight. After cooling to 25° C., the reaction mixture was treated with saturated NaHCO3 (10 ml) and EtOAc (30 ml). The organic layer was separated, washed with brine (10 ml), and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by column chromatography (EtOAc:MeOH=20:1) to give the title compound as an off-white solid (0.145 g, 47%). NMR (400 MHz) 11.96 (br s, 1H), 8.45 (s, 1H), 8.13 (br s, 1H), 8.12 (s, 1H), 7.36 (m, 2H), 7.16 (m, 1H), 6.18 (s, 1H), 5.87 (br s, 1H), 1.95 (d, J=6.8 Hz, 3H), 1.90 (m, 1H), 0.95 (m, 2H), 0.66 (m, 2H). MS: Calcd.: 396. Found: [M+H]+ 397.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[C:7]2[CH:20]=[CH:21][CH:22]=[CH:23][C:6]=2[N:5]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:4](=[O:30])[CH2:3]1.Br[CH2:32][C:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[N:35]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[N:34]=1>CN(C=O)C.C1(C)C=CC=CC=1>[CH2:13]([O:12][C:10](=[O:11])[CH2:9][N:8]1[C:7]2[CH:20]=[CH:21][CH:22]=[CH:23][C:6]=2[N:5]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:4](=[O:30])[CH:3]([CH2:32][C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[N:35]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[N:34]=2)[C:2]1=[O:1])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(CN1C(=O)CC(=O)N(c2ccccc2)c2ccccc21)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2ccccc21
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1nc(CC2C(=O)N(CC(=O)OCc3ccccc3)c3ccccc3N(c3ccccc3)C2=O)c2ccccc21

Procedure:
To a stirring solution of benzyl (2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-1-yl)acetate (3.45 g, 8.62 mM) in 25 mL DMF at 0° C. was added 1.1 equiv. of 0.5 M solution of KN(TMS)2 in toluene. The resulting solution was stirred 10–30 min, then a solution of tert-butyl 3-(bromomethyl)-1H-indazole-1-carboxylate (2.95 g, 9.48 mM) in 15 mL DMF was added. The resulting solution was stirred 2 h at RT and then quenched with 5 mL of H2O. The reaction mixture was then poured into 50 mL of EtOAc and extracted with H2O (2×50 mL). The organic layer was separated, dried (MgSO4), and the solvents removed in vacuo. The resultant material was purified by silica gel flash column chromatography using methylene chloride/EtOAc 9/1 providing 4.4 g of white solid.
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@H:5]([NH2:11])[CH2:4]2.[CH3:12]/[C:13](=[CH:17]\[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)/[C:14](O)=[O:15]>>[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@H:5]([NH:11][C:14](=[O:15])/[C:13](/[CH3:12])=[CH:17]/[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:4]2
Reactant: N[C@@H]1CN2CCC1CC2
Reactant: C/C(=C\c1ccccc1)C(=O)O
Agent: Cl
Product: C/C(=C\c1ccccc1)C(=O)N[C@@H]1CN2CCC1CC2

Procedure:
Prepared as free base by a method analogous to that described in Example 1 from (S)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride and E-α-methyl-3-phenylpropenoic acid; MS (ES+) 271 (MH+).
Reaction SMILES: ClC(Cl)(Cl)CO[C:5]([NH:7][C:8]1[CH:12]=[CH:11][O:10][N:9]=1)=O.OC[C@@H:17]1[O:21][C:20](=[O:22])[N:19]([C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[C:25]([F:35])[CH:24]=2)[CH2:18]1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[O:10]1[CH:11]=[CH:12][C:8]([NH:7][CH2:5][C@@H:17]2[O:21][C:20](=[O:22])[N:19]([C:23]3[CH:28]=[CH:27][C:26]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[C:25]([F:35])[CH:24]=3)[CH2:18]2)=[N:9]1
Reactant: O=C(Nc1ccon1)OCC(Cl)(Cl)Cl
Reactant: O=C1O[C@@H](CO)CN1c1ccc(N2CCOCC2)c(F)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: O=C1O[C@@H](CNc2ccon2)CN1c1ccc(N2CCOCC2)c(F)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 331.2 %

Procedure:
To a stirred solution of 3-(2,2,2-trichloroethyloxycarbonylamino)isoxazole (260 mg, 1.0 mmol), 5(R)-hydroxymethyl-3-(3-fluoro-4-morpholinophenyl)oxazolidin-2-one (see WO 95/07271; 293 mg, 1 mmol) and tributylphosphine (303 mg, 1.5 mmol) in dry tetrahydrofuran (10 ml) at 0° C. under a nitrogen atmosphere, was added 1,1′-(azodicarbonyl)dipiperidine (378.5 mg, 1.5 mmol) in dry tetrahydrofuran (3 ml). The reaction allowed to warm to room temperature and was stirred for 4 days by which time a white suspension had formed. The reaction mixture was filtered and the residue washed with tetrahydrofuran. The filtrate was reconcentrated by rotary evaporation to give a yellow oil (1.2 g) which was purified by MPLC (30% ethyl acetate/hexane, ICN Alumina N 32-63) and further MPLC (100% CH2Cl2, ICN Alumina N 32-63). Concentration of the fractions by rotary evaporation gave the title compound as a crisp white foam (296 mg, 55%). NMR: 2.97 (t, 4H), 3.73 (t, 4H), 3.88 (m, 1H), 4.17 (m, 2H), 4.38 (m, 1H), 5.04 (m, 3H), 6.90 (s, 1H), 7.06 (t, 1H), 7.18(dd, 1H), 7.46 (dd, 1H), 8.91 (d, 1H); m/z ES+ (M+H)=537.
Reaction SMILES: [CH2:1]([OH:12])[C:2]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:4]([O:5][CH3:6])[CH:3]=1.[CH3:13][CH:14]([CH3:24])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21](O)=[O:22].O>CCCCCC>[CH3:13][CH:14]([CH3:24])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:12][CH2:1][C:2]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:4]([O:5][CH3:6])[CH:3]=1)=[O:22]
Reactant: COc1ccc(CO)cc1OC
Reactant: CC(C)CCCCCCC(=O)O
Solvent: O
Solvent: CCCCCC
Product: COc1ccc(COC(=O)CCCCCCC(C)C)cc1OC
Temperature: 50 °C
Yield: 89.1 %

Procedure:
Veratryl alcohol (734 mg, 4.53 mmol), 8-methylnonanoic acid (751 mg, 4.35 mmol) and Novozyme 435 (51 mg) were measured and placed in a flask (25 ml). The mixture was stirred with heating in an oil bath at 50° C. for 16 hr without plugging the flask. After stirring with heating for 2 to 3 hr, attachment of water onto the upper wall of the flask was observed. The reaction mixture was allowed to cool to room temperature, hexane (50 ml) was added, and Novozyme 435 and the insoluble material were removed by filtration. Hexane (25 ml) was added to the filtrate, and the mixture was washed with 5% aqueous citric acid solution (25 ml×2) and saturated brine (25 ml) and dried over anhydrous magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was developed by PTLC (n-hexane:ethyl acetate=3:1), and silica gel containing the object product was stirred with ethyl acetate (100 ml) for 30 min for extraction. The silica gel was filtered off, and the filtrate was concentrated under reduced pressure to give veratryl 8-methylnonanoate (1.25 g, yield 89.1%) as a colorless oil.
Reaction SMILES: [CH:1]([N:4]1[CH2:14][CH:13]2[CH2:15][CH2:16][CH:6]([C:7]3[CH:8]=[CH:9][C:10]([NH2:17])=[CH:11][C:12]=32)[CH2:5]1)([CH3:3])[CH3:2].Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([NH:30][CH3:31])=[O:29])[C:22]([Cl:36])=[CH:21][N:20]=1>>[Cl:36][C:22]1[C:23]([NH:25][C:26]2[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([NH:30][CH3:31])=[O:29])=[N:24][C:19]([NH:17][C:10]2[CH:11]=[C:12]3[C:7](=[CH:8][CH:9]=2)[CH:6]2[CH2:16][CH2:15][CH:13]3[CH2:14][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5]2)=[N:20][CH:21]=1
Reactant: CC(C)N1CC2CCC(C1)c1cc(N)ccc12
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C2CCC3CN(C(C)C)C2)ncc1Cl

Procedure:
2-[5-Chloro-2-(10-isopropyl-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide was prepared from 10-isopropyl-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2(7),3,5-trien-4-ylamine and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide in an analogous manner to Example 271d. Product isolated as a light brown foam (35 mg, 60%). LCMS (m/e) 491 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 11.02 (s, 1H), 8.67 (d, 1H, J=8.4 Hz), 8.09 (s, 1H), 7.47 (dd, 1H, J=1.3 and 7.8 Hz), 7.46-7.42 (m, 2H), 7.33 (d, 1H, J=2.2 Hz), 7.26-7.23 (m, 1H), 7.10-7.03 (m, 1H), 7.00 (d, 1H, J=7.9 Hz), 6.87 (s, 1H), 6.18 (bs, 1H), 3.03 (d, 3H, J=4.9 Hz), 2.98-2.91 (m, 1H), 2.91-2.79 (m, 4H), 2.35-2.30 (m, 2H), 2.18-2.15 (m, 2H), 1.60-1.55 (m, 2H), 0.95 (d, 6H, J=6.6 Hz).
Reaction SMILES: [CH3:1][I:2].[F:3][C:4]([F:16])([F:15])[C:5]1[CH:6]=[C:7]([NH:11][C:12]([NH2:14])=[S:13])[CH:8]=[CH:9][CH:10]=1>O1CCOCC1>[IH:2].[F:16][C:4]([F:3])([F:15])[C:5]1[CH:6]=[C:7]([NH:11][C:12](=[NH:14])[S:13][CH3:1])[CH:8]=[CH:9][CH:10]=1
Reactant: NC(=S)Nc1cccc(C(F)(F)F)c1
Reactant: CI
Solvent: C1COCCO1
Product: CSC(=N)Nc1cccc(C(F)(F)F)c1
Product: I

Procedure:
The starting material for this synthesis is produced as follows: 8 g of methyl iodide in 20 ml of dioxane is added to a solution of 11 g of N-(m-trifluoromethylphenyl)thiourea in 30 ml of dioxane. The reaction mixture is heated for 3 hours on a water bath. The dioxide is evaporated off under reduced pressure, and the residue is recrystallised from a mixture of isopropanol and ethyl acetate to yield N-(m-trifluoromethylphenyl)-S-methylisothiourea-hydroiodide, which melts at 220°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:45])[CH2:4][C@@H:5]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH2:44][CH2:43][CH2:42][C@@:19]3([CH2:23][C@H:22]([O:24][Si](C(C)(C)C)(C4C=CC=CC=4)C4C=CC=CC=4)[CH2:21][CH2:20]3)[CH:18]=2)=[CH:11][CH:10]=1)[C:6]#[C:7][CH3:8].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[CH3:1][O:2][C:3](=[O:45])[CH2:4][C@@H:5]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH2:44][CH2:43][CH2:42][C@@:19]3([CH2:23][C@H:22]([OH:24])[CH2:21][CH2:20]3)[CH:18]=2)=[CH:11][CH:10]=1)[C:6]#[C:7][CH3:8]
Reactant: CC#C[C@@H](CC(=O)OC)c1ccc(OCC2=C[C@]3(CCC2)CC[C@@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C3)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC#C[C@@H](CC(=O)OC)c1ccc(OCC2=C[C@]3(CCC2)CC[C@@H](O)C3)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 86.9 %

Procedure:
To a solution of (3S)-3-{4-[(2R,5R)-2-(tert-butyldiphenylsilanyloxy)-spiro[4.5]dec-6-en-7-ylmethoxy]-phenyl}-hex-4-ynoic acid methyl ester (738 mg) obtained in step 8 in tetrahydrofuran (3.7 mL) was added tetra-n-butylammonium fluoride (1M tetrahydrofuran solution; 2.97 mL), followed by stirring the mixture at room temperature for 17 hours. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane (volume ratio)=1:3) to give (3S)-3-[4-((2R,5R)-2-hydroxy-spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoic acid methyl ester (395 mg).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[CH:9]1(O)[CH2:13][CH2:12][CH2:11][CH2:10]1.OP(O)(O)=O>O.C1(C)C=CC=CC=1>[OH2:2].[CH:9]1([C:6]2[CH:7]=[CH:8][C:1]([OH:2])=[CH:3][C:4]=2[OH:5])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Oc1cccc(O)c1
Reactant: OC1CCCC1
Agent: O=P(O)(O)O
Solvent: Cc1ccccc1
Solvent: O
Product: Oc1ccc(C2CCCC2)c(O)c1
Temperature: 107.5 °C
Reaction time: 1.5 h
Yield: 104.5 %

Procedure:
To a N2 purged pressure reactor is charged resorcinol (44.0 g, 0.40 mol), cyclopentanol (44 mL, 0.49 mol) and 85% aqueous H3PO4 (55 mL, 0.80 mol). The slurry is heated to 95-120° C. for 6-18 hours. The pink reaction mixture is cooled to ˜70° C. and diluted with water (50 mL) and toluene (200 mL). The layers are allowed to separate at 60±5° C. The bottom orange aqueous layer is cut away. The remaining pink organic layer is extracted with 2×50 mL water at 60±5° C. and then stirred with carbon (5 g) at 60±5° C. for 1-2 hours. The slurry is filtered hot through Supercel, rinsing the cake with hot toluene (50 mL). The orange filtrate is diluted with 5 mL water and allowed to cool to ˜30° C. at which time the product crystallizes. The slurry is cooled to 0-5° C. and the product collected, washed with cold toluene (40 mL) and pulled dry on the funnel to afford 41 g of 4-cyclopentyl resorcinol monohydrate as a white to pale pink solid (≧98% area by HPLC). The material can be recrystallized if desired from hot toluene (5 mL/g) and carbon (10% by weight) filtering through Supercel and/or silica gel to the Form I polymorph of 4-cyclopentyl resorcinol afford as a white solid (≧99.7% by HPLC).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[C:15]3[CH:20]=[C:19]([C:21]([OH:23])=[O:22])[CH:18]=[CH:17][N:16]=3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[CH2:29](O)[CH3:30]>>[C:1]1([C:7]2[CH:8]=[CH:9][C:10](/[CH:13]=[CH:14]/[C:15]3[CH:20]=[C:19]([C:21]([O:23][CH2:29][CH3:30])=[O:22])[CH:18]=[CH:17][N:16]=3)=[CH:11][CH:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCO
Reactant: O=C(O)c1ccnc(/C=C/c2ccc(-c3ccccc3)cc2)c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccnc(/C=C/c2ccc(-c3ccccc3)cc2)c1

Procedure:
(E)-2-(4-Phenylphenyl)ethenylpyridine-4-carboxylic acid (3.60 g) and a mixture of concentrated sulfuric acid/ethanol (9:1) were refluxed under heating for 2 hr, and neutralized under ice cooling. The reaction mixture was partitioned between dichloromethane and water, and the aqueous layer was extracted once with dichloromethane. The organic layers were combined, dried over magnesium sulfite and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=9/1-4/1) to give the objective compound (3.14 g) as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:8]=O)[NH:6][N:7]=1)[CH3:2].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([NH2:19])[CH:13]=1.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>C(O)C>[CH2:1]([C:3]1[CH:4]=[C:5]([C:8]2[NH:18][C:15]3[CH:16]=[CH:17][C:12]([O:11][CH3:10])=[CH:13][C:14]=3[N:19]=2)[NH:6][N:7]=1)[CH3:2]
Reactant: COc1ccc(N)c(N)c1
Reactant: CCc1cc(C=O)[nH]n1
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CCc1cc(-c2nc3cc(OC)ccc3[nH]2)[nH]n1

Procedure:
Starting with 100 mg of 5-ethyl-2H-pyrazole-3-carboxaldehyde, 138 mg of 4-methoxy-1,2-phenylenediamine, and 153 mg of sodium metabisulphite, in 1 ml of ethanol and 3 ml of dimethylformamide, and after purification by SPE (SCX phase, washing with methanol, extraction with 2N ammoniacal methanol) followed by a reverse-phase HPLC (5 mm C18 phase, dimensions 100×25 mm, flow rate 20 ml/min, elution gradient: acetonitrile/0.07% TFA—water/0.07% TFA from 5-95 to 95-5 (v/v)), and desalification by SPE (SCX phase, washing with methanol, extraction with 2N ammoniacal methanol), 61 mg of 2-(5-ethyl-2H-pyrazol-3-yl)-5-methoxy-1H-benzimidazole are obtained in the form of a brown lacquer, the characteristics of which are as follows:
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]([CH2:25][CH2:26][CH:27]=C)[C:13]([NH:15][CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:14].[O:29]=[O+][O-]>C(Cl)Cl.CO>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH:12]([CH2:25][CH2:26][CH:27]=[O:29])[C:13]([NH:15][CH2:16][CH2:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:14]
Reactant: C=CCCC(C(=O)NCCCc1ccccc1)N1C(=O)c2ccccc2C1=O
Reactant: O=[O+][O-]
Solvent: CO
Solvent: ClCCl
Product: O=CCCC(C(=O)NCCCc1ccccc1)N1C(=O)c2ccccc2C1=O
Temperature: -78 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
Dissolve 2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3-phenylpropyl-5-hexenylamine (1.2 g, 3.19 mmol) in methylene chloride (40 mL) and methanol (4 mL) and cool to -78° C. under a nitrogen atmosphere. Treat with ozone until a blue color persists, degas with nitrogen for 20 minutes and add pyridine (0.2 mL). Quench with dimethylsulfide (4 mL) and stir overnight at room temperature. Dilute with methylene chloride (75 mL) and wash with 5% sulfuric acid (40 mL) and brine (40 mL) . Dry (Na2SO4), evaporate the solvent in vacuo and purify by chromatography (hexane/ethyl acetate) to give 2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3-phenylpropyl-5-oxo-pentylamine as a white solid (972 mg, 80%).